Lithium is a monovalent cation that can replace Na+ in some biological processes. It can be argued that competition by Li+ for active Na+ sites may lead to altered neuronal functions that may account for its antimanic and mood-stabilizing actions. In this regard, the failure of Li+ to maintain a normal membrane potential because of its lower affinity for the Na+ pump has been demonstrated. However, this action of Li+ would not explain its relatively selective effects on the CNS, sparing comparable excitable tissues (e.g. cardiac muscle) in the periphery. Moreover, an action on membrane polarity would be so general that the entire pool of brain neurons would be affected by Li+. It seems more reasonable that Li+ produces its psychotropic actions by perturbation of molecular events common to a few CNS synapses that might have been disturbed during the course of the manic-depressive illness.
Recently, attention has focused on the actions of Li+ on receptor-mediated second-messenger signaling systems of the brain. In this regard, interactions between Li+ and guanine nucleotide (GTP) binding proteins (G proteins) have been the target of many studies, since G proteins play a pivotal role in the function of many second-messenger signaling systems. Lithium is capable of altering G-protein function. It can diminish the coupling between the receptor recognition site and the G protein. The molecular mechanism involves the competition for Mg++ sites on the G protein, which are essential for GTP binding. Guanine nucleotide activates the G protein.Accordingly, in the presence of Li+, receptor-mediated activation of these G proteins is attenuated. This action of Li+ has been selectively demonstrated for G proteins associated with ^-adrenoceptors and Mj muscarinic receptors of the CNS (Fig. 33.4).
While it is not possible at present to assign a therapeutic role to this action of Li+, it is a step toward explaining the stabilizing actions of this drug. Since several neurotransmitter receptors share common G protein-regulated second-messenger signaling systems, Li+ could simultaneously correct the alterations at individual synapses associated with depression and mania by a single action on the function of specific G proteins.
An additional action of Li+ is interruption of the phosphatidylinositide cycle through an inhibitory action on inositol phosphate metabolism. By this mechanism, depletion of membrane inositol and the phosphoinosi-tide-derived second-messenger products diacylglycerol and inositol triphosphate ultimately reduces signaling through receptor systems dependent on the formation of these products. It is presently unclear to what extent inhibition of inositol phosphate metabolism contributes to the therapeutic properties of Li+ in bipolar patients.
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